While advances have been made in understanding the biology and improving the treatment of ovarian cancer, improved diagnostic and therapeutic approaches are urgently needed. The ability of antibodies to target defined tumor-related structures can improve the selective identification and destruction of tumors. Recent advances in antibody engineering make it possible to structurally modify antibodies to optimize their tumor targeting and effector functions. For example, we have prepared and characterized a recombinant antibody-derived protein consisting primarily of antigen-combining sites (diabody), that targets HER2/neu. This diabody is a non-covalently joined single-chain Fv (scFv)-based dimer that shows exceptional and unique promise in the therapy of HER2/neu overexpressing malignancies. However, HER2/neu is infrequently overexpressed in ovarian cancer. Accordingly, it is necessary to consider different antigen targets to effectively exploit the potential of this novel antibody structural format. It is particularly desirable to target receptors in a manner that disrupts signaling for ovarian cancer growth and survival. The human Mullerian inhibiting substance (MIS) receptor is an attractive candidate target antigen in ovarian cancer. This receptor is expressed in a large percentage of ovarian cancer cell lines and cells isolated from ascites fluid collected from ovarian cancer patients. We have isolated the gene for the MIS type II receptor (MISIIR) extracellular domain (ECD) and have produced the ECD in mammalian cell lines. We hypothesize that high-affinity anti-MISIIR diabodies will efficiently target ovarian cancer, and that these molecules will be effective delivery vehicles for therapeutic radionuclide applications. The aims of this proposal are: 1) To develop human diabody molecules specific for the extracellular domain of the MIS type II receptor; 2) To determine the in vivo targeting and anti-tumor properties of radiolabeled anti-MISIIR diabody molecules; 3) To perform pilot clinical trials that will determine the sensitivity and specificity of (124)I-radiolabeled anti-MISIIR diabody-based targeting in ovarian cancer. By the end of the proposed funding period the data generated by these studies will support the initiation of a pilot, Phase I therapy trial employing a radiolabeled anti-MISIIR diabody for the treatment of ovarian cancer.